Project Summary Lack of preventive and disease modifying treatments for common disorders of the human nervous system is a glaring unmet medical need critical to the mission of NINDS. The work proposed here represents a novel approach to uncover molecular signaling mechanisms underlying temporal lobe epilepsy (TLE). Work accomplished during the current funding period reveals a pivotal role for the brain-derived neurotrophic factor (BDNF) receptor tyrosine kinase,TrkB, in the development of TLE induced by status epilepticus. TrkB-mediated activation of the effector, phospholipase C?1, is the dominant pathway by which TrkB promotes development of TLE. The objective of the current application is to explore the role of TrkB signaling in the persistence of TLE. To accomplish this objective, we will examine the effect of pharmacological and genetic perturbations of TrkB signaling on epilepsy induced in diverse models of TLE. Successful completion of the work proposed may pave the way to preventive and/or disease modifying therapy of TLE, a common disorder of the human central nervous system.